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DLL3靶點新突破:再鼎醫藥公布ZL-1310早期臨床數據!

日期:2024-10-29 14:53:00

DLL3(Delta樣配體-3)作為腫瘤治療中的新興靶點,近年來在小細胞肺癌(SCLC)和神經內分泌腫瘤等領域的研究中備受關注。其在腫瘤細胞中的過度表達和選擇性表達特性,使其成為理想的治療靶點。近期,國內外藥企紛紛加速布局DLL3靶點藥物的研發,尤其是抗體藥物偶聯物(ADC)領域,多筆重磅交易的達成更是將DLL3推向了市場的聚光燈下。2025年元旦前后,信達與羅氏、恒瑞與IDEAYA Biosciences就進行了兩筆授權重磅交易。其中信達生物與羅氏的潛在交易總金額超過10億美元、恒瑞醫藥與IDEAYA Biosciences的潛在交易總金額達10.45億美元。


1、DLL3的結構和功能是什么?

δ樣配體(Delta-Like Ligand 3,DLL3)為一種附著在細胞表面的單次跨膜蛋白,屬于Notch配體家族中的一員。人DLL3基因定位于染色體19q13,其開放閱讀框長度約為1800 bp [3]。人DLL3蛋白由619個氨基酸組成,完整結構包含1個DSL結構域、1個胞內結構域和6個表皮生長因子樣結構域 (圖1[4, 5]。胞外結構域N端的DSL基因序列在配體家族中高度保守,是與Notch受體結合所必須的功能結構域。DLL3胞內結構域較短,其功能尚不清楚。研究發現DLL3在SCLC和其他神經內分泌腫瘤中高表達,而在正常組織中很少表達,這為靶向治療提供了潛力 [6]。近年來,越來越多的研究提示,DLL3可與不同的Notch受體結合,參與到復雜的腫瘤調控過程中,既可表現出促癌作用,也可表現出抑癌作用。

LL3結構示意圖

圖1. DLL3結構示意圖

*圖片來源于Frontiers in immunology 出版物 [4]


2、配體DLL3的受體有哪些?

配體DLL3通過與Notch受體結合,直接或間接地發揮作用生物學功能。Notch受體有4種(Notch 1-4),為一類保守的單次跨膜蛋白,受體分子量約為300 kDa [7]。Notch受體含胞外區、跨膜區和胞內區3部分。如圖2所示,其Notch受體的胞外段(N端)由數量不等的EGF樣重復片段和一個近膜區的負向調節區域(NRR)構成,而NRR是由3個Lin12/Notch重復片段(LNR)和1個異二聚化區域(HD)組成;胞內段通常包含一段蛋白結合RPBJ相關分子(RAM)區域、7個錨蛋白重復片段、1個轉錄激活區域(TAD)和1個PEST(富含脯氨酸、谷氨酸、絲氨酸和蘇氨酸)降解決定子區域 [4]

受體Notch1-4結構

圖2. 受體Notch1-4結構

*圖片來源于Frontiers in immunology 出版物 [4]

不同于Notch其它配體,目前的研究表明DLL3是一種抑制性Notch配體。配體DLL3和Notch受體結合,具有Notch通路的抑制作用 [8]。在SCLC中,促進DLL3表達,DLL3與Notch1受體結合,將抑制Notch信號活化,Notch信號靶基因HES1HEY1的表達下調,對腫瘤的抑制解除,促進SCLC的發生發展 [9];DLL3/Notch2可以增加細胞周期蛋白CyclinD1CyclinD3的表達,提示DLL3/Notch2可能通過上調CyclinD1和CyclinD3蛋白促進SCLC細胞的增殖 [10]。此外DLL3和Notch受體結合還與其它腫瘤密切相關,比如,DLL3/Notch2參與垂體腺瘤的增殖和侵襲的調節 [11];DLL3/Notch2/Notch4對黑色素瘤細胞生存和生長至關重要 [12];DLL3/Notch2/Notch3介導了卵巢癌細胞的增殖和分化,并且與較差的生存期相關 [13]。總體而言,DLL3可與不同的Notch受體結合,在細胞增殖、分化及凋亡中發揮著多種功能,然而其涉及的細胞分子機制仍未具體闡明。


3、DLL3相關的信號通路有哪些?

前文提到,DLL3是一種抑制性Notch配體,大量研究發現,配體DLL3通過和Notch受體結合,抑制Notch信號,影響相鄰細胞之間的通訊,進而調控細胞發育,其具體機制尚不明確。除了Notch信號通路,DLL3也在其他信號通路中發揮作用,DLL3通過抑制Notch信號通路,激活脂酰肌醇-3-激酶/絲氨酸-蘇氨酸蛋白激B(phosphoinositol-3-kinase/serine-threonine protein kinase B,P13K/Akt)信號傳導通路。DLL3表達上調時,配體Wnt-1和Wnt-4以及Wnt通路的下游靶基因Axin-2和Lef-1表達上調,提示DLL3參與誘導Wnt信號途徑的激活。此外,還有研究證實DLL3通過調節Nrarp的循環表達來調節Notch/Wnt信號通路 [14]

由此可見,DLL3參與到多個信號通路中的調節過程,涉及一系列基因的激活、表達以及調控等作用。在腫瘤的發生發展中,DLL3發揮著促癌或抑癌的雙向調節功能。因此,進一步研究DLL3在各腫瘤中的表達和作用機制,將對腫瘤的發病機制、治療和預防等具有重要的意義。


4、DLL3在腫瘤疾病中的作用

根據腫瘤類型和細胞生長環境的不同,DLL3的激活可以發揮促癌或抑癌作用。有報道,DLL3在小細胞肺癌 [15, 16]、乳腺癌 [17]、垂體瘤 [11]、急性髓系白血病 [18]中有促癌作用,但在肝癌 [19]、神經膠質瘤 [20]和惡性膠質瘤 [21]中卻發揮了抑癌作用。

在小細胞肺癌中,DLL3在超過80%患者中高表達,并且在腫瘤的細胞膜和細胞質中都高表達;但是,在正常組織中少量表達或不表達。臨床研究表明,SCLC中的DLL3高表達與患者的生存期呈現負相關,即DLL3表達量越高,患者的生存期越低 [22]

在原發性肝癌中,有研究提示,DLL3的表達被乙肝病毒誘導的DNA甲基化和組蛋白乙酰化所抑制。抑制組蛋白去乙酰化酶的抑制劑可以使DLL3在HCC中重新表達。重表達的DLL3可以抑制HCC細胞的生長并誘導細胞凋亡。因此,在原發性肝癌中,DLL3可以抑制癌細胞的生長 [23]

更多研究顯示DLL3在多種癌癥中異常表達,發揮不同作用。比如,DLL3在異檸檬酸脫氫酶IDH突變的神經膠質瘤細胞中表達,特別是在1p/19q缺失的神經膠質瘤細胞中高表達 [24, 25];在胰腺癌中,激活的DLL3可以刺激Notch信號從而促進癌細胞的生長 [26];在黑色素瘤中,DLL3/MAPK通路可以促進黑色素瘤細胞的增殖和遷移 [27, 28];在子宮內膜瘤中,高表達的DLL3與較差的生存期和較差的無進展生存期相關 [29]


5、靶向DLL3的研發藥物及臨床意義

隨著DLL3 ADC臨床研究的不斷推進和積極數據的不斷涌現,該領域的競爭愈發激烈。中國藥企在這一賽道上的表現尤為引人注目,再鼎醫藥的ZL-1310等藥物在臨床試驗中展現出優異的療效和安全性,有望在國際市場中占據重要地位。未來,隨著更多創新藥物的不斷涌現,DLL3靶點有望為腫瘤患者帶來更多的治療選擇和希望。


6、DLL3科研產品服務

為鼎力協助各藥企針對DLL3靶點在腫瘤中的研發工作,尤其是在小細胞肺癌SCLC中,大量的基礎研究和臨床研究證據表明DLL3是治療SCLC的一種極具潛力的干預靶點,CUSABIO已推出DLL3系列產品,種屬多樣、標簽多樣,能夠充分滿足不同種屬交叉實驗及各類實驗需求,為科研人員提供優質的產品,助力生命科學領域的研究與發展。

DLL3蛋白

Recombinant Human Delta-like protein 3 (DLL3), partial (Active), His-tagged (Code: CSB-MP882142HU3d7)

CSB-MP882142HU3d7 SDS-PAGE

Purity ≥ 95% validated by SDS-PAGE

High Purity Validated of CSB-MP882142HU3d7

Activity validated by Functional ELISA: Measured by its binding ability in a functional ELISA. Immobilized Human DLL3 at 2 μg/ml can bind Anti-DLL3 recombinant antibody (CSB-RA882142MA2HU). The EC50 is 1.107-1.282 ng/mL.

Recombinant Human Delta-like protein 3 (DLL3), partial (Active),Fc-tagged (Code: CSB-MP882142HU2)

CSB-MP882142HU2 SDS-PAGE

Purity ≥ 95% validated by SDS-PAGE

High Purity Validated of CSB-MP882142HU2

Activity validated by Functional ELISA: Measured by its binding ability in a functional ELISA. Immobilized Human DLL3 at 1 μg/ml can bind Anti-DLL3 recombinant antibody (CSB-RA882142MA2HU). The EC50 is 6.211-7.209 ng/mL.

Recombinant Macaca fascicularis Delta-like protein 3 (DLL3), partial (Active),His-tagged (Code: CSB-MP3536MOV)

CSB-MP3536MOV SDS-PAGE

Purity ≥ 85% validated by SDS-PAGE

High Purity Validated of CSB-MP3536MOV

Activity validated by Functional ELISA: Measured by its binding ability in a functional ELISA. Immobilized DLL3 at 2 μg/ml can bind Anti-DLL3 Recombinant Antibody (CSB-RA882142A1HU). The EC50 is 1.625-2.702 ng/mL.


參考文獻:

[1] https://xueqiu.com/4797094524/309486542

[2] https://www.163.com/dy/article/JDVKQLMO0552Q7S2.html?spss=dy_author

[3] Bulman, Michael P., et al. "Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis." Nature genetics 24.4 (2000): 438-441.

[4] Steinbuck, Martin Peter, and Susan Winandy. "A review of notch processing with new insights into ligand-independent notch signaling in T-cells." Frontiers in immunology 9 (2018): 1230.

[5] Hu, Bingxin, et al. "Over-expression of human Notch ligand Delta-like 3 promotes proliferation of human gastric cancer cells in vitro." Nan Fang yi ke da xue xue bao= Journal of Southern Medical University 38.1 (2018): 14-19.

[6] Saunders, Laura R., et al. "A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo." Science translational medicine 7.302 (2015): 302ra136-302ra136.

[7] Stanley, Pamela. "Regulation of Notch signaling by glycosylation." Current opinion in structural biology 17.5 (2007): 530-535.

[8] Chapman, Gavin, et al. "Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis." Human molecular genetics 20.5 (2011): 905-916.

[9] Deng, San-Ming, et al. "The Notch ligand delta-like 3 promotes tumor growth and inhibits Notch signaling in lung cancer cells in mice." Biochemical and biophysical research communications 483.1 (2017): 488-494.

[10] Venkatesh, Deepak, et al. "RhoA-mediated signaling in Notch-induced senescence-like growth arrest and endothelial barrier dysfunction." Arteriosclerosis, thrombosis, and vascular biology 31.4 (2011): 876-882.

[11] Wang, Jianpeng, et al. "EGFL7 participates in regulating biological behavior of growth hormone–secreting pituitary adenomas via Notch2/DLL3 signaling pathway." Tumor Biology 39.7 (2017): 1010428317706203.

[12] Ding, Xiaojie, Fuyao Li, and Li Zhang. "Knockdown of Delta-like 3 restricts lipopolysaccharide-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated epithelial-mesenchymal transition." Life sciences 226 (2019): 149-155.

[13] Jia, Dongyu, et al. "NOTCH2/NOTCH3/DLL3/MAML1/ADAM17 signaling network is associated with ovarian cancer." Oncology letters 17.6 (2019): 4914-4920.

[14] Huang, Jianling, et al. "DLL3 is regulated by LIN28B and miR-518d-5p and regulates cell proliferation, migration and chemotherapy response in advanced small cell lung cancer." Biochemical and biophysical research communications 514.3 (2019): 853-860.

[15] Sabari, Joshua K., et al. "Unravelling the biology of SCLC: implications for therapy." Nature reviews Clinical oncology 14.9 (2017): 549-561.

[16] Vitorino, Philip, et al. "Rova-T enhances the anti-tumor activity of anti-PD1 in a murine model of small cell lung cancer with endogenous Dll3 expression." Translational oncology 14.1 (2021): 100883.

[17] Ayyanan, Ayyakannu, et al. "Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism." Proceedings of the National Academy of Sciences 103.10 (2006): 3799-3804.

[18] Yan, S., et al. "Expression profile of Notch‐related genes in multidrug resistant K562/A02 cells compared with parental K562 cells." International journal of laboratory hematology 32.2 (2010): 150-158.

[19] Maemura, Kentaro, et al. "Delta-like 3 is silenced by methylation and induces apoptosis in human hepatocellular carcinoma." International journal of oncology 42.3 (2013): 817-822.

[20] Turchi, Laurent, et al. "Tumorigenic potential of miR‐18A* in glioma initiating cells requires NOTCH‐1 signaling." Stem Cells 31.7 (2013): 1252-1265.

[21] Jungk, Christine, et al. "Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone." BMC medicine 14.1 (2016): 1-16.

[22] Bauer, Todd M., et al. "ORAL02. 01: safety and efficacy of single-agent rovalpituzumab tesirine, a DLL3-targeted ADC, in recurrent or refractory SCLC: topic: medical oncology." Journal of Thoracic Oncology 11.11 (2016): S252-S253.

[23] Hamamoto, Hiroki, et al. "Delta-like 3 is silenced by HBx via histone acetylation in HBV-associated HCCs." Scientific reports 8.1 (2018): 1-11.

[24] Spino, Marissa, et al. "Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase–mutant glioma." Clinical Cancer Research 25.4 (2019): 1261-1271.

[25] Mizoguchi, Masahiro, et al. "Molecular characteristics of glioblastoma with 1p/19q co-deletion." Brain tumor pathology 29.3 (2012): 148-153.

[26] Song, Hai?Yan, et al. "Expression of Notch receptors and their ligands in pancreatic ductal adenocarcinoma." Experimental and therapeutic medicine 16.1 (2018): 53-60.

[27] Kiniwa, Yukiko, et al. "Delta-like protein 3 promotes proliferation and migration of melanoma via MAPK activation." Journal of Dermatological Science 84.1 (2016): e176.

[28] Nakahara, Satoshi, et al. "AT-rich interaction domain-containing protein 3B has a potential to be a new stem cell marker of melanoma." Journal of Dermatological Science 84.1 (2016): e176-e177.

[29] Wang, Juan, et al. "Upregulated delta-like protein 3 expression is a diagnostic and prognostic marker in endometrial cancer: a retrospective study." Medicine 97.51 (2018).


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